Mist1 Expressing Gastric Stem Cells Maintain the Normal and Neoplastic Gastric Epithelium and Are Supported by a Perivascular Stem Cell Niche

National Institutes of Health (U.S.) (Grants 54CA126513, R01CA093405, R01CA120979, and R01DK052778)

The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is one of the key signaling pathways induced by various receptor-tyrosine kinases Accumulating evidence shows that this pathway is an important promoter of cell growth, metabolism, survival, metastasis, and resistance to chemotherapy Genetic alterations in the PI3K/Akt/mTOR pathway in gastric carcinoma have often been demonstrated Many kinds of molecular targeting therapies are currently undergoing clinical testing in patients with solid tumors However, with the exception of the ErbB2-targeting antibody, targeting agents, including PI3K/Akt/mTOR inhibitors, have not been approved for treatment of patients with gastric carcinoma This review summarizes the current knowledge on PI3K/Akt/mTOR signaling in the pathogenesis of gastric carcinoma and the possible therapeutic targets for gastric carcinoma Improved knowledge of the PI3K/Akt/mTOR pathway in gastric carcinoma will be useful in understanding the mechanisms of tumor development and for identifying ideal targets of anticancer therapy for gastric carcinoma

https://www.mdpi.com/2072-6694/6/3/1441/pdf

The Role of PI3K/Akt/mTOR Signaling in Gastric Carcinoma

Triple-negative breast cancer (TNBC) cells are deficient in estrogen, progesterone and ERBB2 receptor expression, presenting a particularly challenging therapeutic target due to their highly invasive nature and relatively low response to therapeutics. There is an absence of specific treatment strategies for this tumor subgroup, and hence TNBC is managed with conventional therapeutics, often leading to systemic relapse. In terms of histology and transcription profile these cancers have similarities to BRCA-1-linked breast cancers, and it is hypothesized that BRCA1 pathway is non-functional in this type of breast cancer. In this review article, we discuss the different receptors expressed by TNBC as well as the diversity of different signaling pathways targeted by TNBC therapeutics, for example, Notch, Hedgehog, Wnt/b-Catenin as well as TGF-beta signaling pathways. Additionally, many epidermal growth factor receptor (EGFR), poly (ADP-ribose) polymerase (PARP) and mammalian target of rapamycin (mTOR) inhibitors effectively inhibit the TNBCs, but they face challenges of either resistance to drugs or relapse. The resistance of TNBC to conventional therapeutic agents has helped in the advancement of advanced TNBC therapeutic approaches including hyperthermia, photodynamic therapy, as well as nanomedicine-based targeted therapeutics of drugs, miRNA, siRNA, and aptamers, which will also be discussed. Artificial intelligence is another tool that is presented to enhance the diagnosis of TNBC.

/pdf/triple-negative-breast-cancer-a-review-of-conventional-and-38bzdooc8p.pdf

Triple-Negative Breast Cancer: A Review of Conventional and Advanced Therapeutic Strategies

Metastasis is responsible for 90% of cancer-related deaths. Strategies are needed that can inhibit the capacity of cancer cells to migrate across the anatomic barriers and colonize distant organs. Here, we show an association between metastasis and expression of a type I receptor tyrosine kinase-like orphan receptor, ROR1, which is expressed during embryogenesis and by various cancers, but not by normal postpartum tissues. We found that expression of ROR1 associates with the epithelial-mesenchymal transition (EMT), which occurs during embryogenesis and cancer metastasis. Breast adenocarcinomas expressing high levels of ROR1 were more likely to have gene expression signatures associated with EMT and had higher rates of relapse and metastasis than breast adenocarcinomas expressing low levels of ROR1. Suppressing expression of ROR1 in metastasis-prone breast cancer cell lines, MDA-MB-231, HS-578T, or BT549, attenuated expression of proteins associated with EMT (e.g., vimentin, SNAIL-1/2, and ZEB1), enhanced expression of E-cadherin, epithelial cytokeratins (e.g., CK-19), and tight junction proteins (e.g., ZO-1), and impaired their migration/invasion capacity in vitro and the metastatic potential of MDA-MB-231 cells in immunodeficient mice. Conversely, transfection of MCF-7 cells to express ROR1 reduced expression of E-cadherin and CK-19, but enhanced the expression of SNAIL-1/2 and vimentin. Treatment of MDA-MB-231 with a monoclonal antibody specific for ROR1 induced downmodulation of vimentin and inhibited cancer cell migration and invasion in vitro and tumor metastasis in vivo. Collectively, this study indicates that ROR1 may regulate EMT and metastasis and that antibodies targeting ROR1 can inhibit cancer progression and metastasis.

https://cancerres.aacrjournals.org/content/canres/73/12/3649.full.pdf

Targeting ROR1 Inhibits Epithelial-Mesenchymal Transition and Metastasis

Background 
The Dishevelled (Dvl) and Dishevelled-associated activator of morphogenesis 1 (Daam1) pathway triggered by Wnt5a regulates cellular polarity during development and tissue homoeostasis. However, Wnt5a signaling in breast cancer progression remains poorly defined.


Methodology/Principal Findings 
We showed here that Wnt5a activated Dvl2, Daam1 and RhoA, and promoted migration of breast cancer cells, which was, however, abolished by Secreted Frizzled-related protein 2 (sFRP2) pretreatment. Dominant negative Dvl2 mutants or Dvl2 siRNA significantly decreased Wnt5a-induced Daam1/RhoA activation and cell migration. Ectopic expression of N-Daam1, a dominant negative mutant, or Daam1 siRNA remarkably inhibited Wnt5a-induced RhoA activation, stress fiber formation and cell migration. Ectopic expression of dominant negative RhoA (N19) or C3 exoenzyme transferase, a Rho inhibitor, decreased Wnt5a-induced stress fiber formation and cell migration.


Conclusions/Significance 
Taken together, we demonstrated for the first time that Wnt5a promotes breast cancer cell migration via Dvl2/Daam1/RhoA.

/pdf/dvl2-dependent-activation-of-daam1-and-rhoa-regulates-wnt5a-23kacvhjx9.pdf

Dvl2-dependent activation of Daam1 and RhoA regulates Wnt5a-induced breast cancer cell migration.

PI3K/Akt-dependent phosphorylation of GSK3β and activation of RhoA regulate Wnt5a-induced gastric cancer cell migration.

Background
Epidermal growth factor (EGF) signaling is implicated in the invasion and metastasis of hepatoma cells. However, the signaling pathways for EGF-induced motility of hepatoma cells remain undefined.

/pdf/gep100-arf6-is-required-for-epidermal-growth-factor-induced-1mp7wssox7.pdf

GEP100/Arf6 is required for epidermal growth factor-induced ERK/Rac1 signaling and cell migration in human hepatoma HepG2 cells

We found that melatonin could inhibit both EGF- and VEGF-induced monolayer permeability of human umbilical vein endothelial cells, which is related to phosphorylation of vascular-endothelial cadher...

/pdf/effect-of-melatonin-on-egf-and-vegf-induced-monolayer-4mae4l4991.pdf

Effect of melatonin on EGF- and VEGF-induced monolayer permeability of HUVECs

Background Hypoxia/reoxygenation (H/R) in human umbilical vein endothelial cells (HUVECs) induces oxidative stress and eventually leads to vascular injury. Objective The aim of this study was to examine the effect of melatonin on HUVECs injured by H/R and explore the underlying mechanisms. Materials and methods A model of HUVECs under hypoxia/reoxygenation was established. Cell migration and adhesive ability was measured by wound healing and adhesion assays. Cell proliferation was measured by EdU assay. Production of reactive oxygen species (ROS) was evaluated by CM-H2DCFDA staining. Actin cytoskeleton rearrangement was examined by immunofluorescence. Western blotting analysis were used to analyze P38 and HSP27 phosphorylation levels. Results H/R inhibited HUVEC proliferation, cell migratory and adhesive capacities, whereas melatonin (1~100 μM) inhibited these effects in a dose-dependent manner. Melatonin alone did not affect HUVEC viability, however, it inhibited the increase in ROS production and cytoskeleton disruption elicited by H/R, and it dose-dependently prevented H/R-induced upregulation of P38 and HSP27 phosphorylation. In addition, the ROS scavenger N-acetyl-L-cysteine markedly inhibited increased phosphorylation levels of P38 and HSP27 under H/R. Conclusions Melatonin may have a potential clinical effect in trials of H/R-induced vascular injury through its antioxidant property.

Melatonin Protects Against Hypoxia/Reoxygenation-Induced Dysfunction of Human Umbilical Vein Endothelial Cells Through Inhibiting Reactive Oxygen Species Generation.

Ling Yang

Papers

Dvl2-dependent activation of Daam1 and RhoA regulates Wnt5a-induced breast cancer cell migration.

PI3K/Akt-dependent phosphorylation of GSK3β and activation of RhoA regulate Wnt5a-induced gastric cancer cell migration.

GEP100/Arf6 is required for epidermal growth factor-induced ERK/Rac1 signaling and cell migration in human hepatoma HepG2 cells

Effect of melatonin on EGF- and VEGF-induced monolayer permeability of HUVECs

Melatonin Protects Against Hypoxia/Reoxygenation-Induced Dysfunction of Human Umbilical Vein Endothelial Cells Through Inhibiting Reactive Oxygen Species Generation.